Legionella pneumophila (Legionella) is the causative agent of a severe pneumonia called Legionnaires'disease. Legionnaires'disease affects mainly the elderly and immune-compromised individuals. Each year, 8,000-18,000 people with legionellosis are hospitalized in the United States and fatality rates vary from 5% to 30%. Recently, an abrupt increase in the incidence of legionellosis in the United States has been noted, particularly among middle aged adults. Furthermore, recent studies reported that Legionella infection has emerged in AIDS and in cancer patients. Therefore, Legionella infection should be considered in the differential diagnosis of any patient with pneumonia. The replication of Legionella within macrophages is critical for the disease, as mutants defective for intracellular growth in vitro are unable to cause pneumonia in vivo. Human macrophages are susceptible to Legionella infection. Whereas most mouse strains are resistant to Legionella with the exception of the A/J, caspase-1-/- and Ipaf-/- mice. The activation of caspase-1 is provoked by Legionella through the NOD receptor Ipaf, leading to robust phagosome-lysosome fusion and bacterial killing. However, the role of other caspases in Legionella infection is still unknown. Our preliminary results show that upon infection of murine macrophages, some caspases were activated independent of the typical apoptosis pathway. Remarkably, macrophages lacking these caspases allowed substantial Legionella replication. Therefore, we propose to study the effect of activation of certain caspases on the fate of the lung pathogen and understand the mechanism by which these molecules control intracellular infection. This work will reveal a new mechanism for caspase activation and explore a novel biological role for caspases in host defense against an intracellular bacterium. Furthermore, information gained from this study will allow the design of molecules that can target specific caspases to control pulmonary infections. PUBLIC HEALTH RELEVANCE: Legionella pneumophila is a bacterium that can cause severe pneumonia especially in the elderly. It is not known how Legionella persists in the human host cell and multiplies to cause disease. This project will help understand how bacteria establish infection, and how the host cell responds to this intracellular pathogen. Therefore, our aims will lead to better management of intracellular infections.